ES2399009T3 - Therapeutic compounds - Google Patents

Abstract

A compound having the structure or its pharmaceutically acceptable salt, in which: Y is A is - (CH2) 6-, cis -CH2CH> = CH- (CH2) 3-, or -CH2C≡C- (CH2) 3 -, in which 1 or 2 carbon atoms can be replaced by S or O; or A is - (CH2) m-Ar- (CH2) o-, in which Ar is interethylene or heterointerarylene, the sum of m and or 1, 2, 3 or 4, and in which a CH2 can be replaced by S or O; J is C> = O, CHOH, CHF, CHCl, CHBr, or CHCN; and B is 4- (1-hydroxy-2,2-dimethylpropyl) phenyl, 4- (1-hydroxy-2-methylpropan-2-iI) phenyl, 4- (1-hydroxy-2-methylpropyl) phenyl, 4- (1-hydroxybutyl) phenyl, 4- (1-hydroxyheptyl) phenyl, 4- (1-hydroxyhexyl) phenyl, 4- (1-hydroxypentyl) phenyl, 4- (1-hydroxypropyl) phenyl, 4- (3-hydroxy- 2-methylheptan-2-yl) phenyl, 4- (3-hydroxy-2-methyloctan-2-yl) phenyl, 1-hydroxy-2,3-dihydro-1H-inden-5-yl, 2,3-dihydro -1H-inden-5-yl, 3- (hydroxy (1-propylcyclobutyl) methyl) phenyl, 4- (1-hydroxy-5,5-dimethylhexyl) phenyl, 4- (hydroxy (1-propylcyclobutyl) methyl) phenyl, 4-tert-butylphenyl, 4-hexylphenyl, 4- (1-hydroxy-2-phenylethyl) phenyl, 4- (1-hydroxy-3-phenylpropyl) phenyl, 4- (1-hydroxycyclobutyl) phenyl, 4- (2- cyclohexyl-1-hydroxyethyl) phenyl, 4- (3-cyclohexyl-1-hydroxypropyl) phenyl, 4- (cyclohexyl (hydroxy) methyl) phenyl, 4- (cyclohexylmethyl) phenyl, or 4- (hydroxy (phenyl) methyl) phenyl .

Description

Therapeutic compounds

Related request

This application claims the benefit of US provisional application serial number 61 / 034,866, filed on March 5, 2008, and non-provisional US application serial No. 12 / 394,697, filed on February 27, 2009.

Background of the invention

The ocular hypotensive agents are useful for the treatment of a number of various ocular hypertensive disorders, such as ocular hypertensive episodes after surgical and laser trabeculectomy, glaucoma, and as pre-surgical aids.

10 Glaucoma is an eye disease characterized by elevated intraocular pressure. Based on its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) can be open-angle or acute, or chronic by angular closure. Secondary glaucoma arises from pre-existing eye diseases, such as uveitis, intraocular tumor or an extended cataract.

The underlying causes of primary glaucoma are not yet known. The elevated intraocular pressure is due

15 to the obstruction of the outflow of aqueous humor. In chronic open-angle glaucoma, the anterior chamber and its anatomical structures appear normal, but the drainage of aqueous humor is obstructed. In acute glaucoma

or chronic by angular closure, the anterior chamber is shallow, the filtration angle is narrowed, and the iris can obstruct the trabecular meshwork at the entrance to the Schlemm canal. Pupil dilation can push the iris root forward against the angle, and can produce pupillary blockage and thus trigger an attack.

20 sharp. The eyes with narrow anterior chamber angles are predisposed to acute attacks of glaucoma by angular closure of varying degrees of severity.

Secondary glaucoma is caused by any interference in the flow of aqueous humor from the posterior chamber to the anterior chamber and then to the Schlemm canal. An inflammatory disease of the anterior segment can prevent watery outflow causing a complete posterior synechia in the bulging iris and

25 can plug the drain channel with exudates. Other common causes are intraocular tumors, extended cataracts, occlusion of the central vein of the retina, trauma to the eye, surgical procedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in approximately 2% of all people over 40 years of age and can be asymptomatic for years before moving towards the rapid loss of

30 vision In cases where surgery is not indicated, topical adrenoceptor antagonists have traditionally been the drugs chosen to treat glaucoma.

Currently, certain eicosanoids and their derivatives are available in the market for use in the treatment of glaucoma. Eicosanoids and their derivatives include numerous compounds that are biologically important, such as prostaglandins and their derivatives. Prostaglandins can be described as

35 derivatives of prostanoic acid having the following structural formula:

Various types of prostaglandins are known, depending on the structure and substituents on the allylic ring of the prostanoic acid skeleton. Another classification is based on the number of unsaturated bonds in the side chain indicated by the numerical subscript after the generic type of prostaglandin (for example, prostaglandin E1 (PGE1), prostaglandin E2 (PGE2)), and the configuration of alicyclic substituents indicated

40 per year! (for example, prostaglandin F2∀ (PGF2!)).

The prostaglandin E analog shown below is described in the following documents: US Patent No. 5,462,968; U.S. Patent No. 5,698,598; and U.S. Patent No. 6,090,847.

Other selective EP2 agonists are described in US Patent Application Serial No. 11/009298, filed on December 10, 2004 (now Patent No. 7,091,231, issued August 15, 2006). It is believed that selective prostaglandin agonists EP2 have several medical uses. For example, U.S. Patent No.

6,437,146 indicates the use of selective prostaglandin agonists EP2 to treat or prevent inflammation and pain

5 of joints and muscles (for example, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritris, gouty arthritis, juvenile arthritis, etc.), inflammatory skin disorders (for example, sunburn, burns, eczema, dermatitis, etc.), disorders inflammation of the eye (for example, conjunctivitis, etc.), pulmonary disorders in which inflammation is involved (for example, asthma, bronchitis, pigeon fancier disease, farmer's lung, etc.), gastrointestinal tract disorders associated with inflammation (for example, aphthous ulcer, Crohn's disease,

10 atrophic gastritis, varialoform gastritis, ulcerative colitis, celiac disease, regional ileitis, irritable bowel syndrome, etc.), gingivitis, inflammation, pain and tumescence after an operation or injury, pyrexia, pain and other disorders associated with inflammation, allergic disease, systemic lupus erythematosus, scleroderma, polymyositis, tendinitis, bursitis, periarteritis nodosa, rheumatic fever, Sjgren's syndrome, Behcet's disease, thyroiditis, type I diabetes, diabetic complications (diabetic microangiopathy, diabetic retinopathy, nephropathy

15 diabetic, etc.), nephrotic syndrome, aplastic anemia, myasthenia gravis, uveitis, contact dermatitis, psoriasis, Kawasaki disease, sarcoidosis, Hodgkin's disease, Alzheimer's disease, renal dysfunction (nephritis, nephritic syndrome, etc.), liver dysfunction (hepatitis, cirrhosis, etc.), gastrointestinal dysfunction (diarrhea, inflammatory bowel disease, etc.), shock, bone disease characterized by an abnormal bone metabolism, such as osteoporosis (especially postmenopausal osteoporosis), hypercalcemia, hyperparathyroidism bone disease

20 Paget, osteolysis, hypercalcemia of malignancy with or without bone metastases, rheumatoid arthritis, periodonritis, osteoarthritis, ostealgia, osteopenia, cancer cachexia, calculi, lithiasis (especially urolithiasis), solid carcinoma, mesangial proliferative glomerulonephritis, edema (for example , cardiac edema, cerebral edema, etc.), hypertension such as malignant hypertension or the like, premenstrual tension, urinary calculi, oliguria such as that caused by acute or chronic insufficiency, hyperphosphaturia, or the like.

25 US Patent No. 6,710,072 indicates the use of EP2 agonists for the treatment or prevention of "osteoporosis, constipation, kidney disorders, sexual dysfunction, baldness, diabetes, cancer and in immune regulation disorders, ... various diseases pathophysiological diseases that include acute myocardial infarction, vascular thrombosis, hypertension, pulmonary hypertension, ischemic heart disease, congestive heart failure, and angina pectoris. ”

US-A-2005/0176800 refers to substituted pyrrolidine compounds and pharmaceutical compositions comprising these compounds. It is indicated that the compounds described herein are useful for the treatment of a variety of diseases and disorders that include asthma and hypertension.

WO-A-2007/140136 refers to cyclopentane derivatives and their use for the treatment of various ocular hypertensive disorders, such as glaucoma.

Summary of the invention

Compounds useful for treating glaucoma, inflammatory bowel disease, baldness, hair growth stimulation, and stimulation of the conversion of hairy hair to terminal hair are described herein. The compounds themselves are described below.

Description of the invention

40 A compound having the structure is described herein

or its pharmaceutically acceptable salt;

A is - (CH2) 6-, cis -CH2CH = CH- (CH2) 3-, or -CH2C # C- (CH2) 3-, in which 1 or 2 carbon atoms can be replaced by S or O; or A is - (CH2) m-Ar- (CH2) or-, in which Ar is inter-ethylene or hetero-arylene, the sum of m and 5 or is 1, 2, 3 or 4, and in which a CH2 can be replaced by S or O;

J is C = O, CHOH, CHF, CHCl, CHBr, or CHCN; Y

B is 4- (1-hydroxy-2,2-dimethylpropyl) phenyl, 4- (1-hydroxy-2-methylpropan-2-iI) phenyl, 4- (1-hydroxy-2-methylpropyl) phenyl, 4- ( 1-hydroxybutyl) phenyl, 4- (1-hydroxyheptyl) phenyl, 4- (1-hydroxyhexyl) phenyl, 4- (1-hydroxypentyl) phenyl, 4- (1-hydroxypropyl) phenyl, 4 (3-hydroxy-2-methylheptan- 2-yl) phenyl, 4- (3-hydroxy-2-methylctan-2-yl) phenyl, 1-hydroxy-2,3-dihydro-1H-inden-5-yl, 2,3

10 dihydro-1H-inden-5-yl, 3- (hydroxy (1-propylcyclobutyl) methyl) phenyl, 4- (1-hydroxy-5,5-dimethylhexyl) phenyl, 4- (hydroxy (1-propylcyclobutyl) methyl) phenyl, 4-tert-butylphenyl, 4-hexylphenyl, 4- (1-hydroxy-2-phenylethyl) phenyl, 4- (1-hydroxy-3-phenylpropyl) phenyl, 4- (1-hydroxycyclobutyl) phenyl, 4- (2- cyclohexyl-1-hydroxyethyl) phenyl, 4- (3-cyclohexyl-1-hydroxypropyl) phenyl, 4 (cyclohexyl (hydroxy) methyl) phenyl, 4- (cyclohexylmethyl) phenyl, or 4- (hydroxy (phenyl) methyl) phenyl;

or in which the structure is:

In relation to the identity of A described in the chemical structures presented herein, A is - (CH2) 6-, cis -CH2CH = CH- (CH2) 3-, or -CH2C # C- (CH2) 3-, in which 1 or 2 carbon atoms may be replaced by S or O;

or A is - (CH2) m-Ar- (CH2) or-, in which Ar is inter-ethylene or hetero-arylene, the sum of myo is 1, 2, 3 or 4, and in which a CH2 can be replaced by S or O.

Although not intended to be a limitation, A may be - (CH2) 6-, cis -CH2CH = CH- (CH2) 3-, or -CH2C # C- (CH2) 3-.

Alternatively, A may be a group that is related to one of these three moieties, in which any carbon is replaced by S and / or O. For example, although it is not intended to limit the scope of the invention in any way, A it may be a residue in which S replaces one or two carbon atoms, such as one of the following or the like.

Alternatively, although it is not intended to limit the scope of the invention in any way, A may be a moiety in which O replaces one or two carbon atoms, such as one of the following or the like.

Alternatively, although it is not intended to limit the scope of the invention in any way, A may have an O replacing a carbon atom, and an S replacing another carbon atom, such as one of the following or the like.

As an alternative, although it is not intended to limit the scope of the invention in any way, A is - (CH2) m-Ar (CH2) or-, in which Ar is inter-arylene or hetero-arylene, the sum of myo is 1, 2, 3 or 4, and in which a CH2 may be replaced by S or O. In other words, although it is not intended to limit the scope of the invention in any way:

10 in one embodiment, A comprises 1, 2, 3 or 4 residues CH2 and Ar, for example, -CH2-Ar-, - (CH2) 2-Ar-, -CH2-Ar-CH2-, -CH2Ar- (CH2 ) 2-, - (CH2) 2-Ar- (CH2) 2-, and the like;

In another embodiment, A comprises: O; 1, 2 or 3 CH2 residues; and Ar, for example, -O-Ar, Ar-CH2-O-, -O-Ar- (CH2) 2-, -O-CH2-Ar-, or -O-CH2-Ar- (CH2) 2- , and the like; or

In another embodiment, A comprises: S; 1, 2 or 3 CH2 residues; and Ar, for example, -S-Ar, Ar-CH2-S-, -S-Ar- (CH2) 2-, -S-CH215 Ar-, or -S-CH2-Ar- (CH2) 2-, - (CH2) 2-S-Ar, and the like.

In another embodiment, the sum of m and o is 2, 3 or 4, in which a CH2 may be replaced by S or O.

In another embodiment, the sum of m and o is 3, in which a CH2 may be replaced by S or O.

In another embodiment, the sum of m and o is 2, in which a CH2 may be replaced by S or O.

In another embodiment, the sum of m and o is 4, in which a CH2 may be replaced by S or O.

20 An interarylene or heterointerarylene refers to an aryl ring or a ring system, or a heteroaryl ring or a ring system that connects two different parts of a molecule, that is, the two parts are attached to the ring in two ring positions differentiated. The interarylene or heterointerarylene may be substituted or unsubstituted. The unsubstituted interarylene or heterointerarylene has no other substituents other than the two parts of the connecting molecule. The substituted interarylene or heterointerarylene has other substituents in addition to the two

25 parts of the molecule that connects.

In one embodiment, Ar is interphenylene, intertienylene, interfurylene, interpyridinylene, interoxazolylene and substituted or unsubstituted intertiazolylene. In another embodiment, Ar is interphenylene (Ph). In another embodiment, A is - (CH2) 2-Ph-. Although it is not intended to limit the scope of the invention in any way, the substituents may have 4 or less heavy atoms, in which the heavy atoms are C, N, O, S, P, F, Cl, Br and / or I in any stable combination. 30 Any number of hydrogen atoms necessary for a specific substituent can also be included. A

Substituent must be stable enough for the compound to be useful as described herein. In addition to the atoms listed above, a substituent may also have a metal cation or any other stable cation having an atom not listed above, if the substituent is acidic and the salt form is stable. For example, -OH can form a salt -O-Na +, or CO2H can form a CO2-K + salt. Any cation of the

5 salt is not included in the expression "4 or less heavy atoms". Thus, the substituents can be: -hydrocarbyl, having up to 4 carbon atoms, including C4 alkyl, alkenyl, alkynyl and the like; -hydrocarbyloxy, up to C3; -an organic acid, such as CO2H, SO3H, P (O) (OH) 2, and the like, and their salts;

10-CF3; -halogen, such as F, Cl or Br; -hydroxyl; -NH2 and alkylamine functional groups, up to C3; -other substituents containing N or S, such as CN, NO2 and the like;

15 and the like.

In one embodiment, A is - (CH2) m-Ar- (CH2) or-, in which Ar is interphenylene, the sum of myo is 1, 2 or 3, and in which a CH2 can be replaced by S u O. In one embodiment, A is -CH2-Ar-OCH2-. In another embodiment, A is -CH2-Ar-OCH2-, and Ar is interphenylene. In other

embodiment, Ar is attached to positions 1 and 3, also called m-interphenylene, such as when A has the structure shown below.

In another embodiment, A is - (CH2) 6-, cis -CH2CH = CH- (CH2) 3-, or -CH2C # C- (CH2) 3-, in which 1 or 2 carbon atoms can be replaced by S or O; or A is - (CH2) 2-Ph-, in which a CH2 may be replaced by S or O.

In another embodiment, A is - (CH2) 6-, cis -CH2CH = CH- (CH2) 3-, or -CH2C # C- (CH2) 3-, in which 1 or 2 carbon atoms 25 can be replaced by S or O; or A is - (CH2) 2-Ph-.

In other embodiments, A has one of the following structures, in which Y is attached to the aromatic or heteroaromatic ring.

In another embodiment, A is -CH2OCH2Ar. In another embodiment, A is -CH2SCH2Ar.

In another embodiment, A is - (CH2) 3Ar. In another embodiment, A is -CH2O (CH2) 4. In another embodiment, A is -CH2S (CH2) 4. In another embodiment, A is - (CH2) 6-.

5 In another embodiment, A is cis -CH2CH = CH- (CH2) 3-. In another embodiment, A is -CH2C # C- (CH2) 3-. In another embodiment, A is -S (CH2) 3S (CH2) 2-. In another embodiment, A is - (CH2) 4OCH2-. In another embodiment, A is cis -CH2CH = CH-CH2OCH2-.

In another embodiment, A is -CH2CH # CH-CH2OCH2-. In another embodiment, A is - (CH2) 2S (CH2) 3-. In another embodiment, A is -CH2-Ph-OCH2-, in which Ph is interphenylene. In another embodiment, A is -CH2-mPh-OCH2-, in which mPh is m-interphenylene. In another embodiment, A is -CH2-O- (CH2) 4-.

In another embodiment, A is -CH2-O-CH2-Ar, where Ar is 2,5-intertienylene. In another embodiment, A is -CH2-O-CH2-Ar, where Ar is 2,5-interfurylene. In another embodiment, A is (3-methylphenoxy) methyl. In another embodiment, A is (4-but-2-ynyloxy) methyl. In another embodiment, A is 2- (2-ethylthio) thiazol-4-yl.

In another embodiment, A is 2- (3-propyl) thiazol-5-yl. In another embodiment, A is 3-methoxymethyl) phenyl. In another embodiment, A is 3- (3-propylphenyl. In another embodiment, A is 3-methylphenethyl. In another embodiment, A is 4- (2-ethyl) phenyl.

In another embodiment, A is 4-phenethyl. In another embodiment, A is 4-methoxybutyl. In another embodiment, A is 5- (methoxymethyl) furan-2-yl. In another embodiment, A is 5- (methoxymethyl) thiophene-2-yl. In another embodiment, A is 5- (3-propyl) furan-2-yl.

In another embodiment, A is 5- (3-propyl) thiophenyl-2-yl. In another embodiment, A is 6-hexyl. In another embodiment, A is (Z) -6-hex-4-enyl. In another embodiment, A is - (CH2) m-Ar- (CH2) or-, in which Ar is inter-ethylene or hetero-arylene, the sum of m and o is 1,

2, 3 or 4, and in which a CH2 may be replaced by S or O.

In another embodiment, A is - (CH2) 3Ar, -O (CH2) 2Ar, -CH2OCH2Ar, - (CH2) 2OAr, -O (CH2) 2Ar, -CH2OCH2Ar, or - (CH2) 2OAr, in which Ar It is monocyclic interheterorylene. In another embodiment, Ar is intertienylene.

In another embodiment, Ar is intertiazolylene. In another embodiment, Ar is interoxazolylene. In another embodiment, A is 6-hexyl. In another embodiment, A is (Z) -6-hex-4-enyl. The compounds according to each of the structures shown below, and their salts pharmaceutically

acceptable, are contemplated as individual embodiments. In other words, each structure represents a

different realization.

J is C = O, CHOH, CHF, CHCl, CHBr, or CHCN. Therefore, each structure shown below represents an embodiment of a compound that is contemplated individually. Pharmaceutically acceptable salts of the compounds according to the following structures are also contemplated.

Aryl is an aromatic ring or ring system, such as phenyl, naphthyl, biphenyl and the like.

Heteroaryl is an aryl that has one or more atoms of N, O or S in the ring, that is, one or more carbon atoms of the ring are replaced by N, O and / or S. Although it is not intended to be a limitation Examples of heteroaryl include thienyl, pyridinyl, furyl, benzothienyl, benzofuryl, imidizolyl, indolyl and the like.

An aryl or heteroaryl substituent may have up to 20 non-hydrogen atoms, each in any

10 stable configuration, and all necessary hydrogen atoms, in which the non-hydrogen atoms are C, N, O, S, P, F, Cl, Br and / or I in any stable combination. However, the total number of atoms that are not hydrogen over all combined substituents must also be 20 or less. A substituent must be stable enough for the compound to be useful as described herein. In addition to the atoms listed above, a substituent may also have a metal cation or other cation.

15 stable that has an atom not listed above, if the substituent is acidic and the salt form is stable. For example, -OH can form a salt -O-Na +, or CO2H can form a CO2-K + salt. Thus, although it is not intended to limit the scope of the invention in any way, a substituent may be:

-

hydrocarbyl, that is, a moiety consisting only of carbon and hydrogen, such as alkyl, alkenyl, alkynyl and the like, including linear, branched or cyclic hydrocarbyl, and combinations thereof;

20-hydrocarbyloxy, which means O-hydrocarbyl, such as OCH3, OCH2CH3, O-cyclohexyl, etc., up to 19 carbon atoms;

-

other ether substituents, such as CH2OCH3, (CH2) 2OCH (CH3) 2, and the like;

-

thioether substituents, including S-hydrocarbyl and other thioether substituents;

-

hydroxyhydrocarbyl, which means hydrocarbyl-OH, such as CH2OH, C (CH3) 2OH, etc., up to 19 carbon atoms;

Nitrogen substituents, such as NO2, CN and the like, including amino, such as NH2, NH (CH2CH3OH), NHCH3 and the like, up to 19 carbon atoms;

-

carbonyl substituents, such as CO2H, ester, amide and the like;

-

halogen, such as chlorine, fluorine, bromine and the like;

-

fluorocarbyl, such as CF3, CF2CF3, etc .;

30-phosphorus substituents, such as PO32-, and the like;

-

sulfur substituents, including S-hydrocarbyl, SH, SO3H, SO2-hydrocarbyl, SO3-hydrocarbyl, and the like.

The substituted aryl or heteroaryl can have as many substituents as the ring or ring system can carry, and the substituents can be identical or different. Thus, for example, an aryl ring or a heteroaryl ring may be substituted with chlorine and methyl; methyl, OH, and F; CN, NO2, and ethyl; and the like, including any

35 imaginable substituent or combination of substituents possible in light of this description.

The substituted aryl or heteroaryl also includes a bicyclic or polycyclic ring system, in which one or more

Rings are aromatic, and one or more rings are not. For example, indanonyl, indanyl, indanolyl, tetralonyl and the like are substituted aryl. For this type of polycyclic ring system, an aromatic or heteroaromatic ring, but not a non-aromatic ring, must be attached to the rest of the molecule. In other words, in any structure that shows -B here, in which -is a link, the link is a direct link to a phenyl ring.

B is 4- (1-hydroxy-2,2-dimethylpropyl) phenyl, 4- (1-hydroxy-2-methylpropan-2-iI) phenyl, 4- (1-hydroxy-2-methylpropyl) phenyl, 4- ( 1-hydroxybutyl) phenyl, 4- (1-hydroxyheptyl) phenyl, 4- (1-hydroxyhexyl) phenyl, 4- (1-hydroxypentyl) phenyl, 4- (1-hydroxypropyl) phenyl, 4 (3-hydroxy-2-methylheptan- 2-yl) phenyl, 4- (3-hydroxy-2-methylctan-2-yl) phenyl, 1-hydroxy-2,3-dihydro-1H-inden-5-yl, 2,3-dihydro-1H-inden-5 -yl, 3- (hydroxy (1-propylcyclobutyl) methyl) phenyl, 4- (1-hydroxy-5,5-dimethylhexyl) phenyl, 4- (hydroxy (1-propylcyclobutyl) methyl) phenyl, 4-tert-butylphenyl, 4- hexylphenyl, 4- (1-hydroxy-2-phenylethyl) phenyl, 4- (1-hydroxy-3-phenylpropyl) phenyl, 4- (1-hydroxycyclobutyl) phenyl, 4- (2-cyclohexyl-1-hydroxyethyl) phenyl, 4- (3-Cyclohexyl-1-hydroxypropyl) phenyl, 4 (cyclohexyl (hydroxy) methyl) phenyl, 4- (cyclohexylmethyl) phenyl, or 4- (hydroxy (phenyl) methyl) phenyl.

Hydrocarbyl is a residue consisting only of carbon and hydrogen and includes, but is not limited to alkyl, alkenyl, alkynyl and the like, and in some cases aryl and combinations thereof.

Alkyl is a hydrocarbyl that has no double or triple bonds, which includes: linear alkyl, such as methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl and the like; branched alkyl, such as isopropyl, branched butyl isomers (i.e., sec-butyl, tert-butyl, etc.), branched pentyl isomers (i.e., isopentyl, etc.), branched hexyl isomers, and alkyl fragments superior branched; cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc .; and alkyl fragments formed by cyclic and non-cyclic, linear or branched components, which may be attached to the rest of the molecule in any available position, including terminal, internal, or ring carbon atoms.

Alkenyl is a hydrocarbyl having one or more double bonds, which includes linear alkenyl, branched alkenyl, cyclic alkenyl, and combinations thereof in analogy to alkyl.

Alkynyl is a hydrocarbyl having one or more triple bonds, which includes linear alkynyl, branched alkynyl, cyclic alkynyl, and combinations thereof in analogy to alkyl.

Aryl is a substituted or unsubstituted aromatic ring, or a ring system, such as phenyl, naphthyl, biphenyl and the like. Aryl may or may not be a hydrocarbyl, depending on whether it has substituents with heteroatoms.

Arylalkyl is an alkyl that is substituted with aryl. In other words, the alkyl connects the aryl to the rest of the molecule. Examples are -CH2-phenyl, -CH2-CH2-phenyl, and the like. The arylalkyl may or may not be a hydrocarbyl, depending on whether it has substituents with heteroatoms.

Unconjugated dienes or polyenes have one or more double bonds that are not conjugated. They can be linear, branched, or cyclic, or their combinations.

Also combinations of the above are possible.

Thus, each of the following structures is contemplated. These structures, or their pharmaceutically acceptable salts, individually represent a compound that is an embodiment contemplated herein. In other words, each structure represents a different embodiment.

Hypothetical examples of useful compounds are shown below.

Examples of compounds:

The following are hypothetical examples of useful compounds. Example of compound 1. A compound having the structure

18 or its pharmaceutically acceptable salt; And it is

5 A is - (CH2) 6-, cis -CH2CH = CH- (CH2) 3-, or -CH2C # C- (CH2) 3-, in which 1 or 2 carbon atoms can be replaced by S or O ; or A is - (CH2) m-Ar- (CH2) or-, in which Ar is interarylene or heterointerarylene, the sum of m and

or is 1, 2, 3 or 4, and in which a CH2 may be replaced by S or O;

J is C = O, CHOH, CHF, CHCl, CHBr, or CHCN; Y

B is 4- (1-hydroxy-2,2-dimethylpropyl) phenyl, 4- (1-hydroxy-2-methylpropan-2-iI) phenyl, 4- (1-hydroxy-2-methylpropyl) phenyl, 4- ( one

10-hydroxybutyl) phenyl, 4- (1-hydroxyheptyl) phenyl, 4- (1-hydroxyhexyl) phenyl, 4- (1-hydroxypentyl) phenyl, 4- (1-hydroxypropyl) phenyl, 4 (3-hydroxy-2-methylheptan -2-yl) phenyl, 4- (3-hydroxy-2-methylctan-2-yl) phenyl, 1-hydroxy-2,3-dihydro-1H-inden-5-yl, 2,3-dihydro-1H-inden- 5-yl, 3- (hydroxy (1-propylcyclobutyl) methyl) phenyl, 4- (1-hydroxy-5,5-dimethylhexyl) phenyl, 4- (hydroxy (1-propylcyclobutyl) methyl) phenyl, 4-tert-butylphenyl, 4 -hexylphenyl, 4- (1-hydroxy-2-phenylethyl) phenyl, 4- (1-hydroxy-3-phenylpropyl) phenyl, 4- (1-hydroxycyclobutyl) phenyl, 4- (2-cyclohexyl-1-hydroxyethyl) phenyl , 4- (3-cyclohexyl-1-hydroxypropyl) phenyl, 4

15 (cyclohexyl (hydroxy) methyl) phenyl, 4- (cyclohexylmethyl) phenyl, or 4- (hydroxy (phenyl) methyl) phenyl;

or in which the structure is:

Example of compound 7. The compound according to example 1, wherein A is (3-methylphenoxy) methyl. Example of compound 8. The compound according to example 1, wherein A is (4-but-2-inyloxy) methyl.

Example of compound 9. The compound according to example 1, wherein A is 2- (2-ethylthio) thiazol-4-yl. Example of compound 10. The compound according to example 1, wherein A is 2- (3-propyl) thiazol-5-yl. Example of compound 11. The compound according to example 1, wherein A is 3-methoxymethyl) phenyl. Example of compound 12. The compound according to example 1, wherein A is 3- (3-propylphenyl. Example of compound 13. The compound according to example 1, wherein A is 3-methylphenethyl.

Example of compound 14. The compound according to example 1, wherein A is 4- (2-ethyl) phenyl. Example of compound 15. The compound according to example 1, wherein A is 4-phenethyl. Example of compound 16. The compound according to example 1, wherein A is 4-methoxybutyl. Example of compound 17. The compound according to example 1, wherein A is 5- (methoxymethyl) furan-2-yl.

Example of compound 18. The compound according to example 1, wherein A is 5- (methoxymethyl) thiophene-2-yl.

Example of compound 19. The compound according to example 1, wherein A is 5- (3-propyl) furan-2-yl.

Example of compound 20. The compound according to example 1, wherein A is 5- (3-propyl) thiophene-2-yl.

Example of compound 21. The compound according to example 1, wherein A is 6-hexyl.

5 Example of compound 22. The compound according to example 1, wherein A is (Z) -6-hex-4-enyl.

The following are hypothetical examples of compositions, kits, methods, uses and medications that employ the examples of hypothetical compounds.

Composition example:

A composition comprising a compound according to any one of the preceding examples of compounds, wherein said composition is a liquid that is ophthalmically acceptable.

Examples of medications:

The use of a compound according to any one of the above examples of compounds, for the manufacture of a medicament for the treatment of glaucoma or ocular hypertension in a mammal.

The use of a compound according to any one of the above examples of compounds, for the manufacture of a medicament for the treatment of baldness in a mammal.

A medicament comprising a compound according to any one of the preceding examples of compounds, wherein said composition is a liquid that is ophthalmically acceptable.

Example of compound for use:

Any one of the above examples of compounds for use in the treatment of baldness in a mammal.

Kit example:

A kit comprising a composition comprising a compound according to any one of the preceding examples of compounds, a container, and instructions for administration of said composition to a mammal for the treatment of glaucoma or ocular hypertension.

A kit comprising a composition comprising a compound according to any one of the preceding examples of compounds, a container, and instructions for administration of said composition to a mammal for the treatment of baldness.

A "pharmaceutically acceptable salt" is any salt that retains the activity of the compound of origin and does not impart other harmful or adverse effects to the subject to which it is administered and in the context in which it is administered,

30 compared to the compound of origin. A pharmaceutically acceptable salt also refers to any salt that can be formed in vivo as a result of the administration of an acid or other salt.

Pharmaceutically acceptable salts of the acid functional groups may be derived from organic or inorganic bases. The salt may comprise a monovalent or polyvalent ion. Of particular interest are the inorganic ions of lithium, sodium, potassium, calcium, and magnesium. Organic salts can be prepared with amines, in particular

35 ammonium salts, such as mono-, di- or trialkylamines or ethanolamines. Salts can also be formed with caffeine, tromethamine and similar molecules. Hydrochloric acid or some other pharmaceutically acceptable acid may form a salt with a compound that includes a basic group, such as an amine or a pyridine ring.

Those skilled in the art will readily understand that for the administration or manufacture of medicaments, the compounds described herein can be mixed with pharmaceutically acceptable excipients, which are

40 known per se in the art. Specifically, a drug to be administered systemically can be made as a powder, pill, tablet or the like, or as a solution, emulsion, suspension, aerosol, syrup or elixir suitable for oral or parenteral administration or for inhalation.

For medications or solid dosage forms, non-toxic solid carriers include, but are not limited to pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, polyalkylene glycols, talc, cellulose, glucose, sucrose, and magnesium carbonate. Solid dosage forms may not be coated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide sustained action over a longer period. For example, a time delay material, such as glyceryl monostearate or glyceryl distearate, can be used. They can also be coated by the technique described in US Pat. Nos. 4,256,108,

4,166,452, and 4,265,874, to form osmotic therapeutic tablets for controlled release. Liquid pharmaceutically administrable dosage forms may comprise, for example, a solution or suspension of one or more of the present useful compounds and optional pharmaceutical adjuvants in a vehicle such as, for example, water, saline solution, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or a suspension. If desired, the pharmaceutical composition to be administered may also contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents and the like. Typical examples of these auxiliary agents are ethyl acetate, sorbitan monolaurate, triethanolamine, sodium acetate, triethanolamine oleate, etc. Actual methods for preparing these dosage forms are known, or will be apparent to those skilled in the art; for example, see, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 16th edition, 1980. The composition of the formulation to be administered, in any case, contains an amount of one or more of the present compounds useful in an amount effective to provide the desired therapeutic effect.

Parenteral administration in general is characterized by injection, subcutaneously, intramuscularly or intravenously. Injectables can be prepared in conventional forms, such as liquid solutions or suspensions, solid forms suitable for dissolution or suspension in a liquid before injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol and the like. In addition, if desired, injectable pharmaceutical compositions to be administered may also contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like.

The amount of the present compound or useful compounds administered will depend on the desired therapeutic effect or effects, of the particular mammal being treated, the severity and nature of the mammalian disorder, the route of administration, the potency and the pharmacodynamics of the compound. or specific compounds used, and the criteria of the doctor in charge. The therapeutically effective dosage of the present compound or useful compounds may be in the range of about 0.5 or about 1 to about 100 mg / kg / day.

A liquid that is ophthalmically acceptable is formulated so that it can be administered topically to the eye. Comfort should be maximized, although some formulation considerations (eg drug stability) may require less than optimal comfort. In the case where comfort cannot be maximized, the liquid should be formulated so that it is tolerable for the patient for topical ophthalmic use. In addition, an ophthalmically acceptable liquid must be packaged for a single use, or it must contain a preservative to prevent contamination after multiple uses.

For ophthalmic application, solutions or medications are often prepared using a physiological saline solution as the main vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH with a suitable buffer system. The formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.

Preservatives that can be used in the pharmaceutical compositions of the present invention include, but are not limited to benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate. A useful surfactant is, for example, Tween 80. Similarly, various useful vehicles can be employed in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.

Tonicity adjusters may be added as necessary or convenient. These include, but are not limited to salts, in particular sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjuster.

Various buffers and means can be used to adjust the pH with the proviso that the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as necessary.

Similarly, an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

Other components of excipients that may be included in ophthalmic preparations are chelating agents. A useful chelating agent is edetate disodium, although other chelating agents may also be used instead of or in addition to it.

The ingredients are usually used in the following quantities:

Ingredient Amount (% in w / v)

active ingredient about 0.001-5

preservative 0-0.10

vehicle 0-40

tonicity adjuster 1-10

buffer 0.01-10

pH adjuster c.s. pH 4.5-7.5

antioxidant as needed

surfactant as needed

purified water as necessary up to 100%

Applications to stimulate hair growth

In one embodiment, the compounds described herein may be useful for the treatment of baldness and / or hair loss. Alopecia (baldness) is a lack of normal or abnormal hair, and it is mainly a problem

5 cosmetic in humans. It is a deficiency of terminal hair, colored hair of wider diameter that is easily observed. However, in people called bald, although there is a noticeable absence of terminal hair, the skin contains hairy hair, which is thin and colorless hair that may require a microscopic examination to determine its presence. This hairy hair is a precursor to terminal hair.

The compounds described herein can be used for stimulation, such as hair conversion.

10 hairy to grow as terminal hair, as well as to increase the speed of growth of terminal hair. The usefulness of the compounds described herein for hair growth stimulation was discovered as follows.

In the course of treatment of patients with glaucoma, treatment may be appropriate only for one eye. Within the course of daily practice it was discovered that a patient who had been treated with bimatoprost, a prostaglandin analogue, developed longer, thicker and fuller eyelashes in the treated eye than in the untreated eye. After an examination, it was discovered that the difference was very noticeable. The eyelashes were longer and looked denser and fuller in the treated eye. The appearance of the eyelashes on the eyelids of the treated eyes would be quite attractive if it represented a bilateral phenomenon. As a result of their asymmetric nature, long eyelashes only on one side are considered strange from a cosmetic point of view. A systemic examination was performed.

20 as a result of the asymmetric phenomenon. It soon became clear that this altered aspect was not an isolated discovery. Comparison of the patient's eyelids that were receiving bimatoprost in only one eye revealed subtle changes in the adjacent eyelashes and hairs of the side treated with bimatoprost in several patients. Undoubted differences in varying degrees could be identified in the adjacent eyelashes and hairs of all patients who were receiving the drug unilaterally for more than 6 months.

25 The changes in the eyelashes were evident after a superficial inspection of several patients after taking this issue into account. In patients with light colored hair and eyelashes, the differences could only be easily seen using the high magnification and illumination capabilities of a slit lamp biomicroscope. During the follow-up examination of glaucoma, the general attention is immediately focused on the eye itself. As a result of the large increase necessary, only one eye can be observed at the same time, and the eye is

30 observes with an increase so high that the eyelashes are out of focus. With such high increases, asymmetries in the eyelashes between both eyes are unlikely to be noticed, except if a careful systematic comparison of the eyelashes and adjacent hairs of the eyelids of both eyes is performed.

The parameters observed that lead to the conclusion that more robust hair growth occurred in the treatment area after administration of the prostaglandin analog are multiple. They include a greater 35 length of the eyelashes, greater number of eyelashes along the normal eyelash line, greater thickness and luster of the eyelashes, more terminal hair similar to the auxiliary eyelashes in the transition areas adjacent to the growth areas of normal eyelashes, more terminal hairs similar to auxiliary eyelashes in the intermediate and lateral canthal area, greater pigmentation of the eyelashes, greater number, greater length, as well as greater luster and thickness of the fine hair on the skin of the adjacent eyelid and, by last, greater perpendicular angulation of the

40 eyelashes and terminal hairs similar to eyelashes. Therefore, the conclusion that hair growth is stimulated by prostaglandin analogues, such as bimatoprost, is supported not only by evidence of a difference in a single parameter, but based on multiple parameters of hair appearance in areas treated against control areas in many subjects. 22

The compounds described herein are prostaglandin analogs and, therefore, have activities similar to bimatoprost, contain structural similarities, and therefore are expected to stimulate hair growth and conversion of hairy hair to terminal hair. In one embodiment, the compounds described herein can be used for hair growth stimulation. As used herein, hair growth includes hair associated with the scalp, eyebrows, eyelids, beard and other areas of animal skin.

In one embodiment, the compound is mixed with a dermatologically compatible vehicle or carrier. The carrier, which can be used to prepare compositions as described herein, may comprise, for example, aqueous solutions such as, for example, physiological saline solution, oily solutions or ointments. The carrier may also contain dermatologically compatible preservatives such as, for example, benzalkonium chloride, surfactants such as, for example, polysorbate 80, liposomes or polymers, for, and methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone and hyaluronic acid; These can be used to increase viscosity. In addition, it is also possible to use inserts of soluble or insoluble drugs when the drug is to be administered.

In one embodiment, dermatological compositions can be formulated for a topical treatment for hair growth stimulation, which comprise an effective amount of hair growth stimulant of one or more compounds as defined above, and a dermatologically compatible vehicle. The effective amounts of the active compounds can be determined by those skilled in the art, but will vary depending on the compound employed, the frequency of application and the desired result. The compound in general will vary from about 0.0000001% to about 50% by weight of the dermatological composition. Preferably, the compound will vary from about 0.001% to about 50% by weight of the total dermatological composition, more preferably from about 0.1% to about 30% by weight of the composition.

In one embodiment, the application of the present compounds for hair growth stimulation has applications in mammalian species, including humans and animals. In humans, the compounds described herein can be applied, for example, to the scalp, facial beard, head, pubic area, upper lip, eyebrows, and eyelids. In animals raised by their skin, for example minks, the compounds described herein can be applied to the entire body surface to improve the entire skin for commercial reasons. The process can also be used for cosmetic reasons in animals, for example, it can be applied to the skin of dogs and cats that have patches of bare skin due to scabies or other diseases that cause degrees of alopecia.

Pharmaceutical compositions contemplated for hair growth stimulation include pharmaceutical compositions suitable for topical and local action. The term "topical," as used herein, refers to the use of a compound, as described herein, incorporated into a suitable pharmaceutical vehicle, and applied to the site of lightened or bald hair to exert an action. local. Accordingly, these topical compositions include the pharmaceutical forms in which the compound is applied externally by direct contact with the skin to be treated. Conventional pharmaceutical forms for this purpose include ointments, liniments, creams, shampoos, lotions, pastes, jellies, powders, aerosols and the like, and can be applied in patches or bandages impregnated depending on the part of the body to be treated. The term "ointment" includes formulations (including creams) that have oilseed, water-soluble and emulsion bases, for example, petrolatum, lanolin, polyethylene glycols, as well as mixtures thereof.

Generally, the compounds can be applied several times over a sustained period of time, topically, on the part of the body to be treated, for example, the eyelids, the eyebrows, the skin or the scalp. The preferred dosage regimen in general will involve regular administration, for example daily, during a treatment period of at least one month, more preferably at least three months, and most preferably at least six months.

For topical use on the eyelids or eyebrows, the active compounds may be formulated in aqueous solutions, creams, ointments, or oils that show an acceptable physiological osmolarity by the addition of pharmaceutically acceptable buffers and salts. These formulations, depending on the dispenser, may or may not contain preservatives, such as benzalkonium chloride, chlorhexidine, chlorobutanol, para-hydroxybenzoic acids, and phenylmercic salts, such as nitrate, chloride, acetate and borate, or antioxidants, as well as additives, such as EDTA, sorbitol, boric acid and the like, as additives. In addition, in particular the aqueous solutions may contain agents that increase viscosity, such as polysaccharides, for example, methyl cellulose, mucopolysaccharides, for example, hyaluronic acid and chondroitin sulfate, or polyols, for example, polyvinyl alcohol. Various matrices and slow-release gels can also be employed, as well as soluble and insoluble eye inserts, for example, based on substances that form gels in situ. Depending on the actual formation and compound to be used, various amounts of the drug and different dose regimens can be used. Generally, the daily amount of the compound for the treatment of the eyelid may be from about 0.1 ng to about 100 mg per eyelid.

For topical use on the skin and scalp, the compound can be formulated advantageously using ointments, creams, liniments or patches as vehicles of the active ingredient. In addition, these formulations may or may not contain preservatives, depending on the dispenser and the nature of the use. These preservatives include those mentioned above, and methyl-, propyl- or butyl-para-hydroxybenzoic acid, betaine, chlorhexidine, benzalkonium chloride, and the like. Various matrices can also be used for slow release administration. Generally, the dose to be applied to the scalp is in the range of

5 about 0.1 ng to about 100 mg daily, more preferably from about 1 ng to about 10 mg daily, and most preferably from about 10 ng to about 1 mg daily depending on the compound and formulation. To achieve the daily amount of medication that depends on the formulation, the compound can be administered once or several times daily with or without antioxidants.

For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the

10 compound described herein. Topical formulations in general can be formed by a pharmaceutical vehicle, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.

The actual dose of the active compounds of the present invention depends on the specific compound and the disorder to be treated; the selection of the appropriate dose is within the knowledge of those skilled in the art.

The compounds described herein are also useful in combination with other drugs useful for the treatment of glaucoma or another disorder.

Synthetic procedures

Publication of US Patent Application 2005/0176800 describes the preparation of substituted pyrrolidine derivatives 1, 13 and 22 (see Schemes 1-5).

Example 1

20 Pyrrolidine 1 was arylated on nitrogen using aryl halide A using Buchwald / Hartwig reaction procedures to install the chain-! (scheme 1).

Scheme 1

(a) B, Pd (0), ligand, base, solvent; (b) 6M HCl in dioxane; (c) LiOH, H2O, THF; (d) I, ClCO2Et, Et3N, CH2Cl2 2. RCH2CH2OH.

Conventional deprotection and saponification procedures would then produce the desired acid. 4. The arylation can be carried out using a wide variety of substituted bromophenyl compounds and other bromoaryl compounds, which are commercially available or can be prepared according to literature procedures. published. For example, U.S. Patent Application No. 11 / 009,298, issued December 10, 2004, and U.S. Provisional Patent Application 60 / 742,779, issued December 6, 2005, describe methods for preparing a series of Useful substituted bromophenyl compounds. These procedures can also be readily adapted to other bromoaryl compounds, such as substituted bromothienyl, substituted bromofuryl, substituted bromopyridinyl, substituted bromonaphthyl, substituted bromobenzothienyl, and the like. Compound 4 can be converted into compounds 5a or 5b as indicated in Figure 1, a method known to those skilled in the art.

10 in the art.

Example 2

In addition, the hydroxyl of intermediate 3 is protected and the C-9 ketone functionality is manipulated to produce the chloride derivative 9 (scheme 2). Conventional deprotection and saponification procedures would then produce the desired acid 10. Acid 10 then becomes 11a or 11b according to the procedures of the

15 scheme 1.

Scheme 2

(a) TBSOTf, Et3N, CH2Cl2; (b) L-selectride, THF; (c) MsCl, Et3N, CH2Cl2; (d) TBAC, toluene.

Compounds in which J is a CN compound can be prepared by adapting the procedure described in US provisional patent application No. 60 / 747,835, issued May 22, 2006.

Compounds in which J is CHF can be prepared by adapting the procedures described in US Patent Application Serial No. 11 / 009,298, and in US Provisional Patent Application No. 60 / 742,779.

5 Compounds in which J in CHBr can be prepared by adapting the procedures described in Tani, K. et al. (ONO), Bioorganic and Medicinal Chemistry, 2002, 10, 1883.

Example 3

Those skilled in the art can also imagine-chains and-chains. Thus, the aldehyde 12 can be reacted with known phosphonium salts B in a Wittig reaction (scheme 3). The resulting olefin can

10 removed by hydrogenation. The procedures described in the publication of US patent application 2005/0176800 are then used to reach intermediate 17. This intermediate is subjected to conditions similar to those shown in Figure 1 to arrive at arylated product 18 (in which B it is as described in the previous description). The product 18 then becomes 19 according to the procedures of scheme 2. The product 19 then becomes 20a or 20b according to the procedures of scheme 1.

15 Scheme 3

(to)

 D phosphonate, KOtBu or other base, THF; (b) H2, Pd / C, EtOAc; (c) TBAF, THF; (d) Swern oxidation;

(and)

 HC (OMe) 3, H2O4, MeOH.

Example 4

In a hypothetical example, pyrrolidine 21 is rented using electrophile C to produce 22. A deprotection

5 followed by an arylation produces 24, and subsequent manipulations described in Scheme 1 produce the desired acid 26. Acid 26 is then converted to 28a or 28b according to the procedures in Scheme 1. Similar procedures can be performed by replacing C thienyl with phenyl. (i.e., X-CH2-phenyl-CO2H) or other heteroaromatic ring, such as furyl, pyridinyl, etc. These compounds are commercially available, or can be easily prepared by methods recognized in the art.

10 Scheme 4

(to)

 NaH, A, DMF; (b) 3M HCl in dioxane; (c) B, Pd (0), ligand, base, solvent; (d) HF-pyridine, MeCN;

(and)

 LiOH, H2O, THF.

Example 5

In another hypothetical example, pyrrolidine 21 is oxidized using Swern oxidation conditions and then converted to vinyl compound 30. A Grubbs metathesis with olefin D (according to the procedures of US provisional application No. 60 / 777.506, issued on February 28, 2006) produces alkene 31. A hydrogenation, followed by manipulations described in scheme 1, then produces the desired acid 33. D thienyl can be substituted for phenyl and other heteroaromatic rings, such as thienyl, furyl , etc., to produce similar products. The acid 33 is then converted to 34a or 34b according to the procedures of scheme 1.

(a) Swern oxidation; (b) methyleneation of Tebbe; (c) C, Grubbs 2nd generation catalyst, CH2Cl2; (d) H2, Pd / C, EtOAc.

Examples 6 and 7

5 - ((((2S, 3R) -3-Chloro-1- (4- (1-hydroxyhexyl) phenyl) pyrrolidin-2-yl) methoxy) methyl) thiophene-2-carboxylic acid (26) and 510 ( (((2S, 3R) -3-Chloro-1- (4 - ((E) -hex-1-enyl) phenyl) pyrrolidin-2-yl) methoxy) methyl) thiophene-2-carboxylic acid (27)

Stage 1. Alkylation of 21 to produce 22

A solution of 21 (150 mg, 0.64 mmol) and bromide C (179 mg, 0.76 mmol) in DMF (0.45 ml) and THF (1.8 ml) was cooled between -40 ° C and - 20 ° C. Sodium hydride (51 mg, 1.27 mmol) was added discontinuously over 10 min. After 1 h of stirring between -40 ° C and -20 ° C, the reaction was quenched with water (3 ml) and extracted with

CH2Cl2 (4 x 5 ml). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude residue on silica (hexanes: CH2Cl2) gave 169 mg (68%) of 22 as a pale yellow oil.

Stage 2. Deprotection of 22 to produce 23

A flask was charged with 22 (160 mg, 0.41 mmol) and 3M HCl in 1,4-dioxane (0.82 ml) to yield a clear pale yellow solution. After stirring at room temperature for 3 h, the mixture was diluted with

20 CH2Cl2 (5 ml) and quenched with saturated aqueous NaHCO3 (4 ml). The phases were separated and the aqueous phase was extracted with CH2Cl2 (2 x 2 ml). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude residue on silica (MeOH: CH2Cl2) yielded 92 mg (77%) of 23 as a pale yellow oil.

Stage 3. Arilation of 23 to produce 24

Bromide A (107 mg, 0.29 mmol), 23 (100 mg, 0.35 mmol), Pd (OAc) 2 (6.5 mg, 0.029 mmol), racemic BINAP (27 mg, 0.043 mmol), carbonate Cesium (131, 0.40 mmol) and toluene (1.2 ml) were combined in a 12 x 75 mm test tube. The tube was fitted with a septum, purged with nitrogen and placed in an oil bath at 100 ° C. After stirring for 16 h, the mixture was cooled, diluted with EtOAc and filtered through Celite. The filtrate was concentrated in vacuo. Purification of the crude residue on silica (15% hexane% EtOAc / hexanes% EtOAc, gradient) produced 51 mg (31%) of 24 along with 45 mg (45%) of 23 recovered.

Stage 4. Deprotection of 24 to produce 25

Tetrabutylammonium fluoride (0.26 ml of a 1.0 M solution in THF, 0.26 mmol) was added to a solution of 24 (50 mg, 0.088 mmol) in THF (0.6 ml). After stirring for 16 h at room temperature, the solvents were removed under a stream of nitrogen, and the mixture was diluted with EtOAc (20 ml). The organic phase was washed with water (3 x 10 ml) and brine (10 ml), then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude residue on silica (hexane% 40% EtOAc / hexanes, gradient) yielded 13.3 mg (33%) of 25 along with 11.5 mg (23%) of 24 recovered.

Stage 5. Saponification of 25 to produce 26 and 27

Test 1: Lithium hydroxide (0.05 ml of a 1.0 N solution in water, 0.05 mmol) was added to a solution of ester 25 (2 mg, 0.004 mmol) in THF (0.1 ml) in a vial of 3.70 ml, and the mixture was stirred overnight at room temperature. After 16 h, the solvent was removed under a stream of nitrogen, and the mixture was diluted with water (0.2 ml) and acidified with 1.0 N HCl (0.1 ml). The mixture was extracted with EtOAc (3 x 2 ml). The combined extracts were washed with brine (1 ml), dried (Na2SO4), filtered and concentrated in vacuo to yield 1.5 mg of 26 contaminated with removal product 27 (approximately 70% pure by NMR analysis of 1H).

Test 2: Lithium hydroxide (0.09 ml of a 1.0 N solution in water, 0.09 mmol) was added to a solution of ester 25 (8 mg, 0.017 mmol) in THF (0.17 ml), and the mixture was stirred overnight at room temperature. After 16 h, the solvent was removed under a stream of nitrogen, and the mixture was diluted with water (1 ml) and acidified with 1.0 N HCl (0.1 ml). The mixture was extracted with EtOAc (3 x 10 ml). The combined extracts were washed with brine (5 ml), dried (Na2SO4), filtered and concentrated in vacuo to yield a mixture of 26 and 27. Purification of the crude mixture on silica (CH2Cl2% 15% MeOH / CH2Cl2, gradient) produced 2.0 mg (27%) of 26 (27 was not isolated, probably due to decomposition on silica).

Example 8

Stage 1. Arilation of 23 to produce 35

E bromide (74 mg, 0.29 mmol), 23 (100 mg, 0.35 mmol), Pd (OAc) 2 (6.5 mg, 0.029 mmol), racemic BINAP (27 mg, 0.043 mmol), carbonate Cesium (131, 0.40 mmol) and toluene (1.2 ml) were combined in a 12 x 75 mm test tube. The tube was fitted with a septum, purged with nitrogen and placed in an oil bath at 100 ° C. After stirring for 16 h, the mixture was cooled, diluted with EtOAc and filtered through Celite. The filtrate was concentrated in vacuo. Purification of the crude residue on 12 g silica (15% hexane% EtOAc / hexanes% EtOAc, gradient) produced 77 mg (57%) of 35.

Stage 2. Saponification of 35 to produce 36

Lithium hydroxide (0.23 ml of a 1.0 N solution in water, 0.23 mmol) was added to a solution of ester 35 (21 mg, 0.045 mmol) in THF (0.45 ml), and the mixture It was stirred overnight at room temperature. After 16 h, the solvent was removed under a stream of nitrogen, and the mixture was diluted with water (1 ml) and acidified with 0.5 N HCl (2 ml). The mixture was extracted with EtOAc (3 x 10 ml). The combined extracts were washed with brine (10 ml), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude mixture on silica (CH2Cl2% 10% MeOH / CH2Cl2, gradient) yielded 12 mg (59%) of 36.

Stage 3: Conversion of 36 into 37a and 37b

Then, the product 36 is converted into 37a or 37b according to the procedures of scheme 1.

Scheme 6

(a) D, Pd (0), ligand, base, solvent; (b) LiOH, H2O, THF.

Those skilled in the art will understand the meaning of the stereochemistry associated with the characteristics.

5 structural wedge striped / solid wedge. For example, an introductory textbook to organic chemistry (Francis, A. Carey, Organic Chemistry, New York, McGraw-Hill Book Company, 1987, p. 63) states that “a solid wedge indicates a bond that leaves the plane of the paper towards the observer ”, and that the striped wedge, indicated as a“ dashed line ”,“ represents a link that moves away from the observer ”. Unless the stereochemistry is explicitly shown, a structure is intended to include any possible stereoisomer, both pure and in any

10 possible mix.

In vivo examples

The above compounds 5a, 5b, 11a, 11b, 20a, 20b, 28a, 28b, 34a, 34b, 37a and 37b are tested in vivo to measure their ability to reduce intraocular pressure. Compound 5a is tested in normotensive dogs. Intraocular pressure (IOP) decreases from baseline. This compound is also tested in hypertensive monkeys.

15 laser induced, and IOP decreases from baseline.

Compound 5b is tested in normotensive dogs. Intraocular pressure (IOP) decreases from baseline. This compound is also tested in laser-induced hypertensive monkeys, and the IOP decreases from the baseline.

Compound 11a is tested in normotensive dogs. Intraocular pressure (IOP) decreases from baseline.

20 This compound is also tested in laser-induced hypertensive monkeys, and the IOP decreases from the baseline.

Compound 11b is tested in normotensive dogs. Intraocular pressure (IOP) decreases from baseline. This compound is also tested in laser-induced hypertensive monkeys, and the IOP decreases from the baseline.

Compound 20a is tested in normotensive dogs. Intraocular pressure (IOP) decreases from baseline. This compound is also tested in laser-induced hypertensive monkeys, and the IOP decreases from the baseline.

Compound 20b is tested in normotensive dogs. Intraocular pressure (IOP) decreases from baseline. This compound is also tested in laser-induced hypertensive monkeys, and IOP decreases from the line of

30 base.

Compound 28a is tested in normotensive dogs. Intraocular pressure (IOP) decreases from baseline. This compound is also tested in laser-induced hypertensive monkeys, and the IOP decreases from the baseline.

Compound 28b is tested in normotensive dogs. Intraocular pressure (IOP) decreases from baseline.

35 This compound is also tested in laser-induced hypertensive monkeys, and the IOP decreases from the baseline.

Compound 34a is tested in normotensive dogs. Intraocular pressure (IOP) decreases from baseline. This compound is also tested in laser-induced hypertensive monkeys, and the IOP decreases from the baseline.

5 Compound 34b is tested in normotensive dogs. Intraocular pressure (IOP) decreases from baseline. This compound is also tested in laser-induced hypertensive monkeys, and the IOP decreases from the baseline.

Compound 37a is tested in normotensive dogs. Intraocular pressure (IOP) decreases from baseline. This compound is also tested in laser-induced hypertensive monkeys, and IOP decreases from the line of

10 base.

Compound 37b is tested in normotensive dogs. Intraocular pressure (IOP) decreases from baseline. This compound is also tested in laser-induced hypertensive monkeys, and the IOP decreases from the baseline.

Claims (5)

1.-A compound that has the structure or its pharmaceutically acceptable salt, in which: 5 Y is A is - (CH2) 6-, cis -CH2CH = CH- (CH2) 3-, or -CH2C # C- (CH2) 3-, in which 1 or 2 carbon atoms can be replaced by S or O; or A is - (CH2) m-Ar- (CH2) or-, in which Ar is interarylene or heterointerarylene, the sum of m and or is 1, 2, 3 or 4, and in which a CH2 may be replaced by S or O; J is C = O, CHOH, CHF, CHCl, CHBr, or CHCN; Y B is 4- (1-hydroxy-2,2-dimethylpropyl) phenyl, 4- (1-hydroxy-2-methylpropan-2-iI) phenyl, 4- (1-hydroxy-2-methylpropyl) phenyl, 4- ( 1-hydroxybutyl) phenyl, 4- (1-hydroxyheptyl) phenyl, 4- (1-hydroxyhexyl) phenyl, 4- (1-hydroxypentyl) phenyl, 4- (1-hydroxypropyl) phenyl, 4 (3-hydroxy-2-methylheptan- 2-yl) phenyl, 4- (3-hydroxy-2-methylctan-2-yl) phenyl, 1-hydroxy-2,3-dihydro-1H-inden-5-yl, 2,3-dihydro-1H-inden-5 -yl, 3- (hydroxy (1-propylcyclobutyl) methyl) phenyl, 4- (1-hydroxy-5,5-dimethylhexyl) phenyl, 4- (hydroxy (1 15 propylcyclobutyl) methyl) phenyl, 4-tert-butylphenyl, 4-hexylphenyl, 4- (1-hydroxy-2-phenylethyl) phenyl, 4- (1-hydroxy-3-phenylpropyl) phenyl, 4- (1-hydroxycyclobutyl) phenyl, 4- (2-cyclohexyl-1-hydroxyethyl) phenyl, 4- (3-cyclohexyl-1-hydroxypropyl) phenyl, 4 (cyclohexyl (hydroxy) methyl) phenyl, 4- (cyclohexylmethyl) phenyl, or 4- (hydroxy (phenyl) methyl) phenyl; or in which the structure is: 2. The compound according to claim 1, which has the structure 3.-The compound according to claim 1, which has the structure 4. The compound according to claim 1, which has the structure 5. The compound according to claim 1, which has the structure 6. The compound according to claim 1, which has the structure 7. A compound according to any one of claims 1 to 6, for use in the treatment of baldness in a mammal.